The purpose of this proposal is to develop a radioligand development program to discover, test and apply innovative PET radioligands to probe high priority molecular targets implicated in mental illness. This program will build on Molecular Neuroimaging's existing radioligand development laboratory and clinical program to create a robust process to effectively select and test radioligands. We propose to utilize a tiered radioligand development and application strategy with Tier 1 - Chemistry development and in vitro testing, Tier 2 - In vivo assessment in non-human primates, Tier 3-IND acquisition and human proof of concept and validation studies, and Tier 4 - Application to test mechanisms of action, assess brain penetrance, and target occupancy of drug candidates. Depending on the existing data, radioligands may enter the development scheme at any tier if there is sufficient rationale that advancing the radioligand will inform relevant mental health disease mechanisms. The goal is to simultaneously develop multiple radioligands at different tiers as funding allows. We will implement a priori go/no-go decision rules for each development tier recognizing that the risk of failure for any radioligand is greatest at Tier 1 and likelihood of success increases a the ligand progresses from Tier 1 to Tier 4. The program Steering Committee consisting of NIH leadership, MNI scientists, and industry and academic subject-matter experts will nominate radioligand targets, review ongoing data, and manage resource allocation to optimize the program radioligand pipeline. In specific aims 1-3, we propose to develop radiotracers targeting the D1 dopamine receptor, GABA transporter, and PDE2a in collaboration with pharmaceutical colleagues both as examples of key targets for radioligand development for mental health disorders and as a proof of concept for the strategy for a collaborative program for innovative PET radioligand development. The protocols, INDs and data acquired through the proposed PET imaging program will be made available through the MNI website and an existing online resource (SNIDD). PET imaging provides the opportunity to determine the brain distribution of the molecular target, to examine and distinguish target subtypes, to investigate the expression of the target in mental health disorders, and to demonstrate the target occupancy to determine an optimal therapeutic dose of potential therapeutic compounds. The comprehensive radioligand development program is designed to work collaboratively with the pharmaceutical industry, biotech and academics to identify and efficiently assess molecular targets relevant to ultimately accelerate therapeutic development for mental health diseases. Developing tools to demonstrate target engagement is a crucial step in assessing compounds that may probe the pathobiology and/or provide novel therapies for mental health disorders.